Potential Utility of Soluble p3-Alcadeinα Plasma Levels as a Biomarker for Sporadic Alzheimer's Disease

Abstract

Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins (α, β, γ) that share identical localization and function to the amyloid-β protein precursor (AβPP) in the brain. Alcs are proteolyzed in neurons through successive cleavages via secretases, resulting in non-aggregative p3-Alc, where p3 corresponds to the AβPP-fragment. We found p3-Alcα detected in human plasma reflected the pathological process of amyloid-β accumulation in Alzheimer's disease (AD) patients and therefore investigated the utility of p3-Alcα as a plasma biomarker in AD. We measured p3-Alcα plasma levels in 83 sporadic-AD, 18 mild cognitive impaired (MCI), and 24 control subjects using the sandwich-ELISA system. Pooled samples with previously published data (171 AD and 45 controls) were also analyzed. The plasma p3-Alcα concentrations in patients with AD and MCI were significantly higher compared with control subjects (224.7 ± 40.4, 223.3 ± 53.9, and 189.1 ± 32.9 pg/ml, respectively; p = 0.0012). In AD patients, the plasma p3-Alcα concentration significantly correlated with age (r = 0.23, p = 0.037) and serum creatinine levels (r = 0.23, p = 0.0012). Even after adjusting for confounding factors of age, gender, renal function, and ApoE-ε4, high plasma p3-Alcα levels were correlated with significant AD risk, with an odds ratio 1.47 (95% confidence interval: 1.18-1.93, p = 0.0019) for every 10 pg/ml increase. Pooled analysis further confirmed these findings. Increased plasma p3-Alcα, evident in the early stages of cognitive impairment, suggests that Alc metabolites are useful plasma biomarkers of AD.

Decrease in p3‐Alcβ37 and p3‐Alcβ40, products of Alcadein β generated by γ‐secretase cleavages, in aged monkeys and patients with Alzheimer's disease

“…We next examined p3‐Alcβ levels in CSF of patients with AD because levels of p3‐Alcα species changed in CSF and plasma of patients with AD [22,26–28,35]. Subject data information of the three cohorts is summarized (Table 1), and the p3‐Alcβ37 and p3‐Alcβ40 levels were quantified in the CSF of patients with mild cognitive impairment (MCI) and AD along with age‐matched controls (Supplementary Table 1).…”

Specific Triazine Herbicides Induce Amyloid-β42 Production

“…Triazines shift the cleavage pattern of alcadeinsα, another γ-secretase substrate [24][25][26][27][28], in a way similar to the AβPP cleavage shift, suggesting a direct effect on γ-secretase rather than on its substrates. Altogether these data support our hypothesis that the HCE contains products able to modulate γ-secretase activity towards the production of high MW, aggregation-prone, AD-associated amyloids.…”

Phosphorylation of multiple sites within an acidic region of Alcadein α is required for kinesin-1 association and Golgi exit of Alcadein α cargo

“…Alcadein/calsyntenin family proteins (Alcα/Clstn1, Alcβ/Clstn3, and Alcγ/Clstn2) are neuronal type I membrane proteins that are subject to proteolytic processing, primarily by ADAM10/17, to generate a membrane-associated carboxy-terminal fragment (Alc CTF) and a secreted amino-terminal region (sAlc). The Alc CTF is then subjected to secondary cleavage within its membrane-spanning region by the γ-secretase complex ( Hintsch et al , 2002 ; Araki et al , 2003 , 2004 ; Hata et al , 2009 ; Piao et al , 2013 ), as is amyloid β-protein precursor (APP), to generate an intracellular cytoplasmic domain fragment (Alc ICD) and to secrete a nonaggregation-prone p3-Alc peptide that is involved in the pathology of Alzheimer’s disease (AD) ( Hata et al , 2011 , 2012; Konno et al , 2011 ; Kamogawa et al , 2012 ; Omori et al , 2014 ).…”